Cyclin-dependent kinase 4 and 6 (CDK4/6) are a group of serine/threonine kinases that drive cells through G1 into S phase by associating with cyclin D. The “cyclin D-CDK4/6-INK4-Rb pathway” is universally disrupted in human cancer and the alterations accelerating of G1 progression provides a survival advantage to cancer cells. Then, inhibition of CDK4 and CDK6 kinase activity may be a useful anticancer treatment.
LEE011 is a small molecule CDK4/6 inhibitor. It is developed by Novartis for the treatment of breast cancer and melanoma. The clinical form of LEE011 is succinate. LEE011 is currently in Phase III studies, and the Phase III shows positive data. The chemical name of LEE011 is 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, and it has the structural of formula I:

At present, CN103201275A reports a hydrate form and a non-hydrate form of compound I mono-succinate. The hydrate form has poor solubility, lower than 0.5 mg/mL in water. The non-hydrate form has better solubility. The inventor of the present invention discovered that the mono-succinate of the prior art is not stable and will have crystal transformation in high humidity, and it is not good enough for development and storage. At present, there is no other crystalline form of compound I and its salts.
Based on the situation, it is necessary to develop new crystalline forms which has good stability, low hygroscopicity, and is suitable for storage and industrial process. And the new forms should meet the requirements of further drug development.